Cellular expression of two prominent eicosanoid biosynthetic enzymes, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX), is upregulated in adenomatous polyps and colon carcinomas. The current model of eicosanoid-mediated carcinogenesis indicates the rise in COX-2 expression and an associated rise in prostaglandin (PG) formation, e.g. PGE2, supports polyp growth and diminishes survival of patients. Distinct from this model, our investigations focus on a novel role for electrophilic lipids generated during catalysis, rather than stable autocoids that are the end products of catalysis. Specifically, our hypothesis focuses on the reactive intermediates produced by lipoxygenase enzymes: hydroperoxy eicosatetraenoic acids (HPETEs), hydroperoxy octadecadienoic acids (HPODEs), and electrophilic lipids generated by metabolic or spontaneous rearrangement of HPETEs and HPODEs. We also focus on a novel mechanism of irreversible, covalent inactivation of proteins in three key regulatory pathways: i) the selenoprotein glutathione peroxidase (GPx) which reduces hydroperoxy lipids to hydroxy lipids; ii) the Ikappa B kinase and rel family subunits that govern the activation status of NFkappaB, a transcription factor that influences gene expression in coloncytes; and iii) STK11/LKB 1, a tumor suppressor associated with neoplasms of Peutz-Jeghers Syndrome, and a serine threonine kinase with homology to IkappaB kinase. Exposure to reactive chemicals that are risk factors in cancer can occur from the environment, diet, or endogenous metabolic and pathological processes. We draw attention to chronic inflammation as one of these processes. Oxygen and nitrogen radical species, acting as endogenous mutagens, contribute to cancer risks associated with persistent inflammation. The carcinogenic mechanism of these agents is best understood in terms of their direct modification of DNA. However, failure of beta-carotene and other antioxidants to confer any benefit in several recent cancer prevention trials has prompted us to reconsider the following questions which are central to our application: What other molecular pathways account for elevated risk of cancer during inflammation or pre-neoplastic progression in the colon? How might these molecular pathways create risks? How might chemoprevention strategies be re-aligned to modulate these molecular pathways/processes and thereby lower these risks? We propose that upregulation of lipoxygenase enzymes, during chronic inflammation, hastens progression of pre-neoplastic lesions and heightens colon cancer risk. We hypothesize that the mechanisms responsible for this are inhibition of selenoprotein peroxidases (e.g. GPx), tumor suppressors (e.g. p53, STK11/LKB1), and redox-sensitive transcription factors (NFkappaB). These critical regulatory molecules limit cellular and genomic exposure to mutational burdens and influence the morphologically restricted proliferation and differentiation of colonocytes. Inactivation of these regulatory molecules, by electrophilic lipid mediators, antagonizes their beneficial roles.